FACTORS DETRIMENTAL TO PROTEIN METABOLISM
The role of inflammation in the metabolic response to stress has been recognized for a long time [1,3,5▪▪]. The inflammatory response is partially regulated at the level of central nervous system, via cytokines and inflammatory mediators . Immunity includes both innate and specific immune responses. The latter is divided into humoral and cell-mediated components, including the release of antibodies and cytokines. Cytokines can impair multiple body functions causing proteolysis, lipolysis, and weight loss. These effects are mainly due to high levels of both interleukin (IL)-6 and tumor necrosis factor-α (TNF-α). TNF-α has been shown to directly reduce transcription and translation of myofibrillar proteins, including heavy and light chains of myosin and actin, via inhibition of the mammalian target of rapamycin (mTOR) signaling pathway . However, the role of IL-6 remains controversial. Activation of the inflammatory cascade results in production of a characteristic profile of cytokines derived from macrophages and lymphocytes, including IL-6. Healthy skeletal muscle, however, produces also IL-6 during contraction in a way that is uncoupled from TNF-α synthesis . Furthermore, IL-6 can inhibit TNF-α and IL-1, thus limiting the inflammatory effects of TNF-α, including hypercatabolism.
Immobilization negatively influences all steps of protein synthesis (transcriptional, translational, and post-translational), translation being the most affected . The regulation of translation induction is mediated by the protein kinase mTOR system which includes at least two different complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) . The mTOR pathway integrates cell signals, including nutrient availability, hypoxemia, and inflammation and interacts with growth factors such as insulin-like growth factor-1 (IGF-1), in the translational process for protein synthesis . Thus, downregulation of this pathway plays a pivotal role in immobilization-related muscle mass loss. Recent studies in animal models demonstrated that immobilization transiently reduces IGF-1 mRNA levels and adenosine monophosphate-activated protein kinase activity, causing severe muscle atrophy [3,5▪▪]. Prolonged immobilization also stimulates degradation of muscle protein by different proteolytic systems, including the nuclear factor-kappaB (NF-κB) pathway, the ubiquitin–proteasome pathway, the calcium-dependent calpains, the caspase-3 system, and the lysosomal proteases [3,5▪▪].
Critical illnesses cause increased activation of the sympathetic nervous system, associated with important hormonal changes such as altered pituitary hormone secretion. In addition, a state of peripheral resistance to anabolic stimuli from growth hormone and insulin is observed. This altered hormonal milieu strongly affects protein and also energy and fat metabolism . Adipokines from fat tissue (i.e., leptin, resistin, and adiponectin) are also considered potential inducers of the metabolic changes observed in acute diseases, most likely through an induction of a higher resistance to anabolic signals . The effects of adipokines on protein kinetics need further studies.
FACTORS ENHANCING PROTEIN METABOLISM
Adequate protein intake is relevant in acute illness to meet the increased requirement for amino acids observed in the patients. This abnormality is due to anabolic resistance and to accelerated rates of protein synthesis supporting the acute-phase response and tissue repair . In septic patients on total parenteral nutrition, muscle protein breakdown was increased up to 160% in comparison to healthy controls. In contrast, protein synthesis was within normal range . Amino acid availability is a major stimulus for protein synthesis. In a recent study in critically ill patients, during the first week of hospitalization, Liebau et al.[13▪▪] showed that parenteral administration of a supplemental amount of amino acids, infused over 3-h, improved whole-body protein balance through stimulation of synthesis, without increasing amino acid oxidation.
Latest clinical guidelines for acute care recommend a protein intake in the range of 1.2–1.5 g/kg/day [14,15]. These intake levels were associated with lower mortality rates [16▪,17,18▪,19▪▪]. In most randomized controlled trials, protein or amino acids were administered with fixed protein-to-energy ratios. Intakes of mixed nutrients (i.e., protein and energy) above the recommended levels have been clearly associated with negative outcomes such as delayed recovery and greater muscle wasting [5▪▪,20–23]. It has been suggested that a higher nutrient intake may negatively interfere with autophagy; but this is an important process, through which dysfunctional and toxic proteins, organelles and even intracellular pathogens are isolated, transported into lysosomes and degraded [5▪▪,24]. Autophagy, not only eliminates noxious substances and pathogens, but also provides nutritional substrates. Autophagy is particularly important in septic patients because it allows the disposal of harmful pathogens [5▪▪,24]. A recent study [19▪▪] used a prospective database to investigate at day 4 (early feeding) from ICU admission, the impact of protein intake levels, above or below 1.2 g/kg/day, on the outcome of 843 mixed medical-surgical critically ill patients, with or without sepsis, on prolonged mechanical ventilation (>72 h). The effects of protein intake levels were evaluated separately from those of energy. The results indicate that the relation between quantity of protein feeding and mortality rates changed according to patient's clinical condition (presence or absence of sepsis) and level of energy provision (overfeeding and nonoverfeeding). In the nonseptic, nonenergy overfed patients, mortality decreased with higher protein intake from 37% for an intake less than 0.8 g/kg, to 35% for 0.8–1.0 g/kg, 27% for 1.0–1.2 g/kg, and 19% for at least 1.2 g/kg/day. In patients with sepsis or energy overfeeding, on the other hand, a higher protein provision did not change the mortality rate. These results were confirmed by an observational study . The efficacy of protein availability seems, therefore, to depend on multiple factors including type of illness, severity of protein catabolism, amount of energy, and timing and dose of supplementation. Further studies are required to define and optimize the complex interplay among these variables.
Leucine and the other branched-chain amino acids
Branched-chain amino acids (BCAAs), leucine (LEU), isoleucine, and valine are known to stimulate muscle protein synthesis and to decrease catabolism. These effects have been attributed mainly to LEU. A concomitant adequate intake of isoleucine and valine, however, is also necessary. Indeed, LEU activates the branched-chain keto acid dehydrogenase (the degradation step for BCAAs), thus reducing concentrations of the other two BCAAs [25▪]. The metabolic effects of BCAAs on proteins are mediated by an activation of the mTOR pathway. In particular, LEU stimulates protein synthesis via activation of the mTORC1  and upregulates the initiation of mRNA translation process . Stress conditions are associated with resistance to the amino acid anabolic effect, which could be caused by alteration in mTORC1 responsiveness [26,28] and/or changes in transmembrane LEU transport. Altered LEU signaling is proportional to illness severity . LEU transport into the cell is mostly regulated by the activity of LEU/GLN antiport L-type amino acid transporter 1 and the glutamine (GLN) transporter sodium-dependent neutral amino acid transporter 2. Experimental models of sepsis have shown that modification in GLN availability may reduce the activity of these transporters, thereby reducing LEU entrance into the cells. Despite a potentially positive effect of BCAA supplementation, a clinical benefit of long-term BCAA treatment has not yet been demonstrated. Such discrepancies can be related to poor study design (e.g., patient heterogeneity, poor nutritional management, etc.)  and/or to the fact that BCAAs are not depleted in critical illnesses .
β-Hydroxy-β-methylbutyrate (HMB) is an active metabolite of leucine, which modulate muscle protein metabolism, possibly preventing muscle mass loss during bed rest and chronic diseases [29▪,30▪]. The role of this anabolic supplement in critical illness has been scarcely investigated. In a randomized, double-blinded study [30▪] 100 trauma ICU patients on isocaloric, isonitrogenous enteral nutrition were divided into the following groups: first, HMB, receiving 3 g HMB; second, HMB+, receiving 3 g HMB plus 14 g of both arginine and glutamine; and third, controls, receiving a placebo product. Nitrogen balance improved in both HMB and HMB+ groups but the HMB+ group maintained a more negative nitrogen balance, suggesting that the addition of arginine and/or glutamine may decrease the HMB effect. HMB did not affect muscle protein breakdown as assessed by urinary 3-methyl histidine. In another study [30▪], 3 g/day of HMB were administered to 34 ventilated chronic obstructive pulmonary disease (COPD) patients over 7 days. The results confirmed potential anticatabolic effects of HMB. Both studies, however, exhibited methodological limitations due to low sensitivity and specificity of markers of protein metabolism. Recently, Deutz et al.[29▪] evaluated in a multicenter, randomized, double-blind trial, the effects of a high-protein oral nutritional supplement, containing HMB (intervention group, n = 328) against placebo (control group, n = 324) in malnourished elderly patients, hospitalized for congestive heart failure, acute myocardial infarction, pneumonia, or COPD. HMB supplementation for 90 days decreased mortality and improved nutritional status. The authors suggested cause–effect relationships between protein accretion and clinical outcome.
Omega-3 fatty acids
Omega-3 fatty acid (n3-FA) supplementation has been shown to improve the anabolic efficiency of protein nutrition and exercise in aging and in patients with chronic diseases or cancer . These n3-FA effects could be related to their known anti-inflammatory action and/or to a direct action on the mTOR signaling pathway . Enteral diets supplemented with fish oils have been tested in patients with acute lung injury and acute respiratory distress syndrome. A meta-analysis showed a 60% mortality reduction when n3-FA were administered continuously with full enteral nutrition [5▪▪]. A more recent meta-analysis does not confirm such benefits . Differences in administration routes and in intestinal absorption and/or lack of interaction with other anabolic stimuli (e.g., exercise or protein supplements) may explain discrepancies among clinical studies .
Only few studies have evaluated the anabolic effects of exogenous insulin administration on muscle protein metabolism in ICU patients. High or submaximal levels of insulin supply improved nitrogen balance by inducing an increased protein synthesis. At high insulin doses, this effect was sustained by an improved rate of inward transport of amino acids, which is severely deficient in critically ill patients [33,34▪,35]. Despite the fact that insulin can be considered a useful anabolic factor, high doses of this hormone are associated with increased risk of hypoglycemia.
Insulin resistance and hyperglycemia have been associated with increased muscle catabolism in severely burned individuals [33,34▪,35]. Metformin in ICU patients lowers blood glucose levels by reducing hepatic glucose production and intestinal absorption as well as by increasing glucose uptake and utilization by peripheral tissues  with a minimal risk of hypoglycemia . Shepherd et al.[34▪] describe the results obtained with metformin treatment in a randomized study on severely burned adults during the acute period after injury. Data showed that metformin decreased endogenous glucose production and increased glucose clearance and oxidation. Furthermore, muscle protein synthesis rate was increased with no changes in protein breakdown. Thus, metformin-mediated suppression of glucose production in the liver was paralleled by reduced net amino acid release from skeletal muscle. This suggests a strong link between insulin resistance and protein kinetics in critical illness. Indeed, insulin infusion during metformin treatment further increased the rate of muscle protein synthesis. Nevertheless, due to the risk of lactic acidosis , larger studies are needed to test safety and efficacy of metformin in long-term treatment of acute diseases.
Propranolol is a nonselective β-blocker, which decreases heart rate, myocardial oxygen consumption, and resting energy expenditure in acute patients. Recent reviews [33,34▪,35] described human studies evaluating the use of propranolol to decrease muscle wasting by blocking adrenergic stimulation. Pediatric patients with burn injuries involving more than 40% of the total body surface area were randomized to receive either propranolol (total average of 6.3 mg/kg/day for 2 weeks) or no treatment. Propranolol did not alter skeletal muscle proteolysis, as assessed by phenylalanine appearance, but increased protein synthesis, as measured by intracellular phenylalanine utilization. Net muscle protein balance was positive in the intervention group, with no significant changes in the inward and/or outward transport of phenylalanine from skeletal muscle, whereas it remained negative in controls. Changes in protein synthesis were associated with reduction in resting energy expenditure and better preservation of lean body mass. Considering that available data are limited, the effects of long-term propranolol treatment on muscle protein metabolism in acute patients need to be confirmed.
Oxandrolone is a synthetic analog of testosterone with minimal virilizing effects that has been tested in acute patients [33,34▪,35]. Oxandrolone supplementation in burned patients was associated with greater lean body mass at discharge, as compared with controls (76 vs. 71%; P < 0.05). Such a protein-sparing effect was mainly the result of a 45% decrease in the rate of muscle protein breakdown, accompanied by lower outward transport of amino acids from skeletal muscle. In another study, burned children received oxandrolone (0.1 mg/kg body weight) twice a day for 7 days. In contrast to burned adults, the improvement in protein net balance, over the intervention period, was due to a 140% elevation in muscle protein synthesis rather than to a decrease in protein breakdown. The apparent discrepancy observed between children and adults about the mechanism of the anabolic effect of oxandrolone may be related to a greater capacity for protein synthesis during childhood [33,34▪,35].
Recombinant human growth hormone
In critical illness, recombinant human growth hormone (rhGH) administration exhibits anabolic effects, possibly mediated by stimulation of insulin-like growth factor-binding protein-3 and IGF-1 synthesis in the liver. Therapy with rhGH has been tested in few ICU studies. rhGH in acute patients improved nitrogen balance, promoted accretion of lean body mass, and decreased wound healing time . In a 5-day trial in 20 surgical acute patients, treatment with rhGH (0.3 IU/kg/day) versus placebo was associated with an increased protein content and muscle protein synthesis. In another study, rhGH (0.43 IU/kg/day) given to 20 patients for 12 days again caused significant accretion of lean body mass without improving muscle function. Neither studies showed effects on the mortality rate. On the other hand, a supplementation trial in critically ill nonburned adults, with rhGH (0.3 IU/kg/day) for 21 days showed increased morbidity and mortality (40%) [33,34▪,35]. Differently from adults, in burned children, in the acute hypermetabolic phase, no significant adverse effects were reported from rhGH supplementation while it improved net protein balance [33,34▪,35]. Muscle protein synthesis increased by 2.4-fold, whereas protein breakdown did not change. Insulin at a dose of 250 mU/m2 did not further stimulate protein synthesis or changed breakdown or net balance in the rhGH-treated patients, while it significantly improved protein synthesis and net balance in controls. These findings suggest that insulin and rhGH may work via a common mechanism, because no additive or synergistic effects on muscle protein synthesis have been shown. rhGH could exert direct anabolic effects in skeletal muscle or through stimulation of IGF-1 and/or elevation of plasma insulin levels .
It is well known that physical activity improves muscle protein metabolism, strength, and function and may decrease oxidative stress and inflammation. These effects play an important role not only in chronic diseases but also in acute conditions. Lately a new syndrome called ‘ICU-acquired weakness’ has been defined to describe the poor physical and functional conditions seen in patients, even after several months from ICU discharge [2,7▪]. Physical activity therapy in ICU patients could prevent or even reverse these impairments [7▪,9]. In fact, early physical rehabilitation in critically ill patients significantly improved peripheral and respiratory muscle strength, quality of life, physical function and ventilator-free days, and reduced hospital stay . However, no significant effect on mortality was detected . This study, in addition to other previous investigations, suggests that physical therapy in an ICU setting could be an important component of care [7▪]. An early application of physical activity programmes, however, poses several difficulties in severely ill patients. Recently, Dirks et al.[39▪▪] investigated the efficacy of neuromuscular electrical stimulation, applied twice a day, to prevent muscle loss in six fully sedated ICU patients. The intervention was applied to one leg, using the other limb as control. After a 7-day intervention period, the authors observed no muscle atrophy in the stimulated leg with an increased mTOR phosphorylation (+19% when compared with baseline, P < 0.05). Severe muscle wasting was found in the control limbs [39▪▪]. Electrical stimulation of muscles seems to be a promising solution to preserve muscle mass in critical illness. Nonetheless, the effect of neuromuscular electrical stimulation on the maintenance of muscle strength remains to be defined.
The complex metabolic response associated with stress causes activation of catabolic factors and resistance to anabolic signals, leading to extensive muscle wasting and to loss of muscle function (Fig. 1). This has been recently quantified in 15–25% of total muscle mass during the first 10 days following admission to ICU [4,5▪▪,6,11]. Such a loss of muscle mass is more pronounced in patients with multiple-organ dysfunction and is associated with poorer outcome . Cause–effect relationships between protein catabolism and mortality have not been proved yet. However, muscle wasting is a key feature and determinant of the ‘ICU acquired weakness’ syndrome. Therefore, preserving lean body mass as well as skeletal muscle quality and function are important targets for long-term outcome and quality of life in patients surviving from critical illness. These goals can probably be achieved through the combination of optimal nutritional support, early mobilization, and, possibly, pharmacological and nutraceutical interventions.
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Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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A well-done review on the positive and negative effects of specific amino acid supplementation in ICU patients.
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29▪. Deutz NE, Matheson EM, Matarese LE, et al. Readmission and mortality in malnourished, older, hospitalized adults treated with a specialized oral nutritional supplement: A randomized clinical trial. Clin Nutr 2016; 35:18–26.
Interesting trial evaluating the effects of protein and HMB supplementation in acute elderly patients.
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Exhaustive review article on the effects of HMB supplementation in ICU.
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39▪▪. Dirks ML, Hansen D, Van Assche A, et al. Neuromuscular electrical stimulation prevents muscle wasting in critically ill comatose patients. Clin Sci (Lond) 2015; 128:357–365.
Attractive intervention study exploring the effects of neuromuscular stimulation in acute patients with assessment of functional and mechanicistical outcomes.
Keywords:Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
critical illness; pharmaconutrients; physical therapy; protein breakdown; protein synthesis